Although it is suggested in the art i) that the blockage of CXCR7 employed along with CXCR4 blockage may be useful for the treatment of SDF-1-dependent tumor progression and metastasis (R B Maksym et al., 2009, The role of stromal-derived factor-1—CXCR7 axis in development of cancer, European Journal of Pharmacology, 625 (1-3), pages 31-40) and ii) that some small molecular inhibitors, such as CCX733 or CCX266, siRNA and blocking antibodies (clones 11G8, 9C4 see e.g. US20070167443; clone 358426 (R&D Systems); 8F11 (Biolegend)), may be useful for therapeutic interference with CXCR4-mediated activation of integrins (T N Hartmann et al., 2008, A crosstalk between intracellular CXCR7 and CXCR4 involved in rapid CXCL12-triggered integrin activation but not in chemokine-triggered motility of human T lymphocytes and CD34+ cells, Journal of Leukocyte Biology, 84, pages 11301140), the biology of CXCR7 is still poorly understood since the mechanism(s) of action through which CXCR7 acts is unclear since i) it may act as a kind of decoy or signalling receptor depending on cell type—R M Maksym et al., supra and since ii) the interplay between ITAC and SDF-1 binding to CXCR7 is unclear.
The identification of selective therapeutically effective anti-CXCR7 agents is not only challenging because of its poorly understood biology (such as e.g. mechanism of action e.g. of the potential agonists CCX733 or CCX266 versus antagonists, interplay with CXCR4, recognition of important epitopes, cross-reactivity of the compounds CCX733 or CCX266 and associated toxicity), it is also acknowledged in the art (see e.g. Naunyn-Schmied Archives Pharmacology 379: 385-388) that the generation of an anti-GPCR therapeutic agent such as an anti-CXCR7 agent is difficult since i) the native conformation of active CXCR7 in cancer cells is not exactly known, since ii) it is expected that CXCR7 shows low immunogenicity (due to a limited number of extracellular surface exposed amino acid residues that are in addition very conserved, e.g. mouse-human CXCR7 is 96% homologues).
Furthermore, compounds (CCX733, CCX754) selectively blocking binding of CXCL11 and CXCL12 to CXCR7 function like chemokine ligands with respect to homodimerization, i.e. enhance CXCR7 homodimerization by 2.5 to 3.5 fold with significant increases (P<0.05) first detected at 10 and 100 nM (K E Luker et al., 2009, Imaging chemokine receptor dimerization with firefly luciferase complementation, FASEB journal, 23, pages 823-834).
Targeting serum albumin to extend the half-life of biological molecules such as e.g. immunoglobulin single variable domains has been described e.g. in WO2008/028977.
The generation of a conventional anti-CXCR7 antibody has been described e.g. in WO2006116319 for conventional antibodies 11G8, 6E10 and in Zabel et al. for conventional antibody 8F11 (Zabel et al., 2009, Elucidation of CXCR7 mediated signalling events and inhibition of CXCR4 mediated tumor cell transendothelial migration by CXCR7 ligands. J Immunol.; 183 (5):3204-11). However, it is unclear at present whether these or similar antibodies are suitable for a medical application